21-4-20151

(1)

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GLP1 receptor agonists:

current status of development

Bruce H.R. Wolffenbuttel, internist‐endocrinologist University Medical Center Groningen Dept. of Endocrinology: www.umcg.net

Blog: www.gmed.nl Twitter: @bhrw

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Disclosure statement

Relevant relationships (last 5 years)

(Company) names

•Bv. Sponsorship or research support

•Bv. Honorarium or other (financial) compensation.

•Eur. Committee: KP7 EU grant (Meerdere)

•DiabetesFonds NL

•Juvenile Diabetes Research Foundation

•NWO

•Min VWS, AZ, Econ Affairs

•Provinces Groningen, Friesland, Drenthe

•Nierstichting (Kidney Foundation)

•Zon MW

•MENZIS

•EASD / EFSD

•AstraZeneca

•Becton Dickinson

•Eli Lilly

•Thermo‐Fisher

•Novo Nordisk

•Roche

•Sanofi Aventis

•Boehringer Ingelheim

•Bayer

I do not receive any honorarium for this lecture The complete presentation can be downloaded from

http://www.gmed.nl/lezingen

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• Current therapy is not perfect

• Important studies with GLP1 receptor agonists

• Can GLP1 agonists modify natural course of T2DM ?

• Long‐term and real‐world data are needed to really really really judge the merit of GLP1 treatment

• Some thoughts on costs of T2DM treatment

• A small personal wish list

Presentation outline

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Treatment of type 2 diabetes:

a stairway to heaven ?

Lifestyle Metformin

Triple medication R/

Complex insulin Simple insulin Dual medication R/

Several drug choices:

Sulphonylurea Thiazolidinediones DPP‐4 inhibitors GLP1 receptor agonists SGLT2 inhibitors

Do not forget, T2DM integrative approach includes:

BP lowering Cholesterol lowering Weight reduction Secondary prevention

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There are no Dutch guidelines for internists;

instead we use the 2015 updated ADA‐EASD recommendations

Inzucchi SE, et al. Diabetes Care 2015;38:140‐149

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Or those of the AACE

https://www.aace.com/files/aace_algorithm.pdf

(2)

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Individualize!! Current treatment algorithms are of limited help in caring for individuals with T2DM.

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1. Hypoglycaemia 2. Weight gain

3. Interference with normal life 4.

5. 6. Injections 7.

..

21. Brussels sprouts

What patients don't like

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Current therapy is not perfect

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What if the UKPDS had stopped after 3‐4 years …

0.6

0.4

0.2

0.0

3 6 9 12 15

Proportion of patients with events

Conventional (411) Intensive (951) Metformin (342)

0

Years from randomisation

Mv I P=0.0034

Remember:

These data apply to recently diagnosed diabetes w. obesity!

Mv C P=0.0023

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Metformin is a cheap BG‐lowering without promoting weight gain, but also without (significant) effect on CVD

If you want to prescribe an SU, probably gliclazide is associated with lowest incidence of hypoglycaemia SU lower BG, but stimulate appetite, increase body weight, may provoke nasty hypoglycaemia, and higher CVD incidence (RR 1.26)

Boussageon et al, PlosONE 2012; Phung et al, Diab Med 2014; Schopman et al, DMRR2014

Metformin and SU in T2DM

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The CIMT‐study: insulin+metformin vs.

insulin+placebo

(3)

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Insulin treatment in type 2 diabetes is associated with:

• Increase in body weight

• Hypoglycaemia but also:

• Heart rhythm disturbances ¹  related to hypoglycaemia

• Sodium retention and  BP ^2,3

• Inflammation of the vascular wall ^4,5  obesity & insulin resistance

• Mitogenic effects ^6,7  insulin growth‐factor

• Inflammation of adipose tissue ⁸  influx macrophages

Insulin: the best there is ??

1. Chow E, et al. Diabetes 2014; 63: 1738‐47; 2. Kanoun F, et al. Diabetes Metab. 2001; 27:695‐700 3. Sarafidis PA, Am J Nephrol 2007; 27: 44‐54; 4. Andersson CX, et al. Diabetes Metab Res Rev 2008; 24: 595‐603 5. Barrett EJ, Liu Z. Rev Endocr Metab Disord 2013; 14: 21‐7; 6. Lundby A, et al. J Appl Toxicol. 2014. doi: 10.1002/jat.3082 7. Rostoker R, et al. Endocr Relat Cancer 2015; 22: 145‐57; 8. Jansen HJ, et al, Diabetologia 2013; 56: 2573‐81

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Insulin use and dose is associated with increased risk of CVD and mortality

Currie CJ, et al. J Clin Endocrinol Metab 2013;98:668‐677 120

80 60 40 20

0

Insulin + metformin

Event rate (per 1,000 person‐years)

Low dose Mid dose High dose

Insulin only and insulin+metformin Insulin

only 18.0 19.320.1

34.6 42.7

54.0 56.6

63.4 78.4

Insulin + metformin Insulin only and

insulin+metformin Insulin only 43.0 44.3

54.9 60.9

71.6 81.4 80.6

95.3

All‐cause mortality Combined endpoint

39.6

“In T2DM, exogenous insulin may be associated with increased risk of diabetes‐related complications”

100

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Insulin use and dose is associated with increased risk of CVD and mortality

Currie CJ, et al. J Clin Endocrinol Metab 2013;98:668‐677 120

80 60 40 20 0

Event rate (per 1,000 person‐years)

Low dose Mid dose High dose

Insulin only and insulin+metformin

Insulin only 18.0 19.320.1

34.6 42.7

54.0 56.6

63.4 78.4

Insulin only and insulin+metformin

Insulin only 43.0 44.3

54.9 60.9

71.6 81.4 80.6

95.3

All‐cause mortality Combined endpoint

39.6

“In T2DM, exogenous insulin may be associated with increased risk of diabetes‐related complications”

100

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Come in these new guys

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Classification of GLP‐1 receptor agonists according to chemical structure

Gorgojo‐Martinez JJ. Hipertens Riesgo Vasc 2014;31:45‐57

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• Early: instead of metformin ?

• 2nd stage: combi treatment in metformin failure ?

• 3rd stage: instead of insulin after failure of oral agents ?

• 4th stage: in combination with existing insulin therapy ?

• How about early combination therapy ?

When can GLP‐1 receptor agonists be used?

(4)

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GLP1 agonist or multiple insulin injections after basal insulin:

4B study

Participants:

•T2DM HbA1c 7.0‐10% op Glargine + metformin 108 clinics, 17 countries (EU, S.Korea, Mex, Arg, Russia)

Week

Optimization of Insulin Glargine

12‐wk BIO Phase

0 30

30‐wk Intervention phase GLP1 receptor agonist 2dd10mcg

Insulin analogue 3x daags Glargine + MF continued

‐14 ‐12

Diamant M, et al, Diabetes Care 2014

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GLP1 agonist or multiple insulin injections after basal insulin:

4B study results

Diamant M, et al, Diabetes Care 2014

INS

EXE

better HRQOL

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Can GLP1 receptor agonists modify the natural course of T2DM ?

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Woman, 59 years, type 2 diabetes

Type 2 diabetes, since 6 yrs Weight 90 kg BMI 30kg/m² intolerant for metformin;

R/ gliclazide + sitagliptin simvastatin normal bloodpressure

stop sitagliptin;

start GLP1 rec. agonist, is paying this HERSELF 100 Euro per month

Goal: glycaemic improvement but wants to loose weight

Does not consider insulin to be an option

Weight 75 kg (BMI 25) No hypo’s No side‐effects

(5)

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Obesity – a risk factor for many chronic disorders

‘Metabolic consequences’

Diabetes Cardiovascular disease

‘Dynamic consequences’

Arthrosis/arthritis/gout Pulmonary complaints Sleep apnoea Esophageal reflux

‘Cancer’

Various types of cancer

‘Other’

Gall stones Alzheimer’s disease Cognitive disturbances Outcome of car accidents Postoperative complications

‐5 ‐ ‐15 kg during GLP1 RA therapy = fewer long‐term sequelae ??

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Possible scenarios regarding body weight benefit of GLP1 agonists

105 100 95 90

85

0 10 30

Body weight (kg)

20 Time (years)

Insulin Scenario 1 Scenario 2 Scenario 3

Long‐term reduction of consequences of excess body weight ??

'Metabolic' / 'Dynamic' / 'Cancer' / 'Other'

Metformin + SU vs. Metformin + sitagliptin;

can DPP4 inhibitor therapy postpone insulin therapy ?

Blonde L, et al. Diabetes 2014

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Treatment with DPP4‐inhibitor sitagliptin will postpone the transition to insulin therapy

Blonde L, et al. Diabetes 2014

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Long‐term and real‐world data are needed to really

really really judge the merit of GLP1 treatment

(6)

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'Real World' experiences

Thong KY, et al. Br J Diab Vasc Dis 2014;14:52‐59

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Patients in the ABCD Nationwide Exenatide and Liraglutide Audit

n=12,955

Exenatide n=6,717 n=2,487

n=1,882

Non‐insulin n=1,027

Insulin n=400 n=1,427

BMI 25‐50 kg/m² n=559

Liraglutide n=6,238 n=1,221

n=1,023

Non‐insulin n=495

Insulin n=353 n=848

BMI 25‐50 kg/m² n=478

Total exenatide and liraglutide patients

Patients with 20‐32 week HbA1c and excluding exenatide switching to liragutide and liraglutide 1.8 mg Patients with 20‐32 week HbA1c and 20‐32 week weight

Patients using exenatide or liraglutide as add‐on therapy

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HbA1c reduction with GLP1 agonists:

also beneficial effect when BMI <35 kg/m

²

‐0.0

‐0.2

Mean HbA1c change (%)

‐0.4

‐0.6

‐0.8

‐1.0

‐1.3

‐1.4

‐1.6

Exenatide Liraglutide

(n=20)

‐1.15 (n=123)

‐1.17 (n=185)

‐1.12 (n=157)

‐0.95 (n=74)

‐1.25 (n=31)

‐1.25 (n=129)

‐1.36 (n=146)

‐1.11 (n=110)

‐0.67 (n=62)

‐0.75

Data analysed by ANCOVA using BMI group and number of OAD as fixed effects, and baseline HbA1c, age, gender, ethnicity as covariates.

Exenatide; P=0.67 for effect of BMI group, liraglutide; P=0.024 for effect of BMI group BMI (kg/m²)

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Body weight reduction with GLP1 Agonist:

also beneficial effect when BMI <35 kg/m

²

0

‐8

Mean weight change (kg)

‐4

‐6

‐8

‐10

Exenatide Liraglutide

(n=22)

‐3.6 (n=117)

‐4.6 (n=193)

‐5.5 (n=157)

‐7.3 (n=76)

‐8.0 (n=31)

‐1.8 (n=130)

‐1.4 (n=146)

‐2.8 (n=101)

‐3.1 (n=62)

‐4.1

Data analysed by ANCOVA using BMI group and number of OAD as fixed effects, and age, gender, ethnicity as covariates.

Exenatide; P<0.001 for effect of BMI group, liraglutide; P=0.021 for effect of BMI group BMI (kg/m²)

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Retrospective analysis of U.S. health insurance claims data from the IHCIS IMPACT database, which contains medical and pharmacy claims, eligibility data, and laboratory results from 86.4 million covered patients.

Of these, 63.7 million (74%) have pharmacy benefits and 12.6 million (15%) have laboratory results; the database includes all data for individuals in all U.S. census regions and represents 46 health plans.

Dalal MR, et al. Endocr Pract 2015

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(7)

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Objection, your honor

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Some final thoughts on costs of type 2 diabetes treatment

(8)

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Long‐term costs of diabetes treatment

Quality‐adjusted life‐year (QALY):

1. measure of disease burden, including both the quality and the quantity of life lived 2. the number of years of life that would be added by an intervention

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• Retrospective administrative claims including medical claims, pharmacy claims, laboratory data, from large, US health plan

• Probability of diabetes complications using the UKPDS outcomes model

• age, sex, ethnicity, smoking, BMI, HbA1c, SBP, lipids, PVD, atrial fibrillation, ischemic heart disease, and congestive heart failure; and blindness at diagnosis

• Probability of death from other cause estimated based on the US 2007 mortality tables

Methodology

Zhang Y, et al. Diabetes Care 2014;37:1338‐1345

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QALY vs. Costs

Δ

met+sulf+insulin met+DPP‐IV+insulin

Expected QALYs prior to the first event

64.34 64.36 64.40

2100 2300 2500 2700 2900

Expected medication cost per QALY (USD/QALY) 64.38 7%

64.32 64.28 64.30

64.26 64.24

6.5%

8%

A B

68.38 68.40 68.44

2100 2300 2500 2700 2900

Expected medication cost per QALY (USD/QALY) 68.42 7%

68.36 68.32 68.34 68.30 68.26

6.5%

8%

met+GLP‐1+insulin met+insulin

QALYs vs. cost incurred by the four different treatment regimens as a function of glycemic control goal. Comparison of the expected QALYs vs. the expected medication cost per QALY incurred from diagnosis to first event (diabetes‐related complication or death) for men (A) and women (B). Each of the four treatments is compared as the glycemic control goal is varied from 6.5% (48 mmol/mol) to 8% (64 mmol/mol). Results are presented using HbA1c of 6.5% (48 mmol/mol) ( ),

7% (53 mmol/mol) ( ), and 8% (64 mmol/mol) ( ) as the glycemic control goal

Men Women

68.28

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How the figure should really look like!!

Expected QALYs prior to the first event

100 300 500 700 900 B

68.38 68.40 68.44

2300 2500 2700 2900 68.42 7%

68.36 68.32 68.34 68.30 68.26

6.5%

8%

68.28

1100 1300 1500 1700 1900 2100

met+sulf+insulin met+DPP‐IV+insulin met+GLP‐1+insulin met+insulin

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• Only predicts 1st event of any diabetes‐related complications

• Does not allow series of events

• Does not incorporate morbidities, like neuropathy or foot ulceration

• Hypoglycaemia and hyperglycaemia also excluded

• No single allowance for other co‐morbid conditions, like COPD, osteo‐arthritis, depression ……. & those associated with obesity, which are predicted to be less with GLP1 RA therapy

Drawbacks of the UKPDS Model

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• Glycaemic effects BMI>35 kg/m2 restriction not backed by evidence

• Health‐related quality of life

• incl. daily activities & work Patients prefer GLP1RA vs insulin

• Effects on diabetic complications Longer term studies needed, but existing therapies not perfect

• Time to insulin dependence Will postpone insulin

• Side‐effects Risk of pancreatitis in real world

• weight increase & hypoglycaemia experience not substantiated

• pancreatic and other organ safety

• Long‐term costs of: Inclusive models needed to assess

• other medications, other co‐morbidities & obesity‐associated disorders

their complications

• absenteeism from work, unemployment, social support

21-4-20151

GLP1 receptor agonists:

current status of development

Disclosure statement

I do not receive any honorarium for this lecture The complete presentation can be downloaded from

http://www.gmed.nl/lezingen

• Current therapy is not perfect

• Important studies with GLP1 receptor agonists

• Can GLP1 agonists modify natural course of T2DM ?

• Long‐term and real‐world data are needed to really really really judge the merit of GLP1 treatment

• Some thoughts on costs of T2DM treatment

• A small personal wish list

Presentation outline

Treatment of type 2 diabetes:

a stairway to heaven ?

There are no Dutch guidelines for internists;

instead we use the 2015 updated ADA‐EASD recommendations

Or those of the AACE

Individualize!! Current treatment algorithms are of limited help in caring for individuals with T2DM.

1. Hypoglycaemia 2. Weight gain

3. Interference with normal life 4.

5.

6. Injections 7.

..

..

21. Brussels sprouts

What patients don't like

Current therapy is not perfect

What if the UKPDS had stopped after 3‐4 years …

Metformin and SU in T2DM

The CIMT‐study: insulin+metformin vs.

insulin+placebo

Insulin: the best there is ??

Insulin use and dose is associated with increased risk of CVD and mortality

Insulin use and dose is associated with increased risk of CVD and mortality

Come in these new guys

Classification of GLP‐1 receptor agonists according to chemical structure

• Early: instead of metformin ?

• 2nd stage: combi treatment in metformin failure ?

• How about early combination therapy ?

When can GLP‐1 receptor agonists be used?

GLP1 agonist or multiple insulin injections after basal insulin:

4B study

GLP1 agonist or multiple insulin injections after basal insulin:

4B study results

INS

EXE

Can GLP1 receptor agonists modify the natural course of T2DM ?

Woman, 59 years, type 2 diabetes

Obesity – a risk factor for many chronic disorders

Possible scenarios regarding body weight benefit of GLP1 agonists

Long‐term reduction of consequences of excess body weight ??

'Metabolic' / 'Dynamic' / 'Cancer' / 'Other'

Metformin + SU vs. Metformin + sitagliptin;

can DPP4 inhibitor therapy postpone insulin therapy ?

Treatment with DPP4‐inhibitor sitagliptin will postpone the transition to insulin therapy

Long‐term and real‐world data are needed to really

really really judge the merit of GLP1 treatment

'Real World' experiences

Patients in the ABCD Nationwide Exenatide and Liraglutide Audit

also beneficial effect when BMI <35 kg/m

also beneficial effect when BMI <35 kg/m

Long‐term costs of diabetes treatment

Methodology

QALY vs. Costs

How the figure should really look like!!

Drawbacks of the UKPDS Model

Things to consider when assessing LONG‐TERM effectivity and

costs of GLP1‐based therapies